Sage Journals: Discover world-class research

Abstract

Esophageal cancer is amongst the most common types of cancer in Asia. It is a deadly disease where incidence almost parallels mortality. It is of 2 major subtypes, adenocarcinoma being more common in the global north and squamous cell carcinoma being more common in the global south. China, Japan, India, Iran, and other Asian countries contribute to roughly 80% of the global disease burden. Fortunately, esophageal squamous cell cancers (ESCC) are also amenable for screening. Natural history studies have shown that severe dysplasia carries the highest risk of progression to ESCC. Early detection has shown to be extremely beneficial, with cure rates above 90% for precursor lesions and early-stage esophageal cancer. There are various modalities available for screening—Chinese balloon cytology is a low cost technique that can be applied for mass screening but has only moderate sensitivity (39%-62%). Recent studies have demonstrated that using methylated DNA markers and applying artificial intelligence technology can significantly improve the yield of cytology. Lugol’s chromo-endoscopy has been demonstrated to have good sensitivity and specificity (>85%), but is an invasive technique and requires operator expertise. Other image enhancing techniques such as narrow-band imaging, autofluorescence, endocytoscopy and micro-endoscopy are promising, but currently not cost effective for mass screening. There are 3 large randomized trials underway in China, initial published results have demonstrated a detection rate between 0.7% to 1.2% for ESCC and 4% to 6% for pre cursor lesions. These trials, with some of them involving >100 000 patients have demonstrated the feasibility of endoscopic screening, but long term results are awaited.

Keywords

esophageal cancer squamous cell carcinoma screening chromo-endoscopy

Introduction

Esophageal cancer is a dreaded malignancy, where the mortality parallels its’ incidence, with esophageal cancer being the eighth most common cancer worldwide and the sixth most common cause of cancer related mortality.¹ It accounted for 3.1% of all solid tumors and 5.5% of cancer related deaths internationally.² There has been a consistent increase in the incidence of esophageal cancer worldwide. As per GLOBOCAN predictions based on current trends, there is a likely to be around 60% increase in esophageal cancer incidence by 2040 as shown in Figure 1.^2-4

Figure 1.

Global projections for 2040 continent wise: (a) estimated new cases in 2020 and projections to 2030 and 2014 and (b) estimated deaths in 2020 and projections to 2030 and 2040. (Borrowed with permission from Prof. Pengfei Xu).⁴

Esophageal cancer is predominantly of 2 histological types—squamous and adeno carcinoma. Other histological types are relatively rare. World over 604 100 cases of esophageal cancer were diagnosed in 2020, with approximately 80% of cases being contributed by Asian countries as shown in Figure 2.¹

Figure 2.

Pie-chart showing proportion of disease distribution continent wise. Borrowed with permission from Prof. Pengfei Xu.⁴

There is a dramatic regional variation in the incidence of these 2 types of esophageal cancers. In Western nations with predominant Caucasian populations, adenocarcinoma is the most common type, accounting for >90% of esophageal cancers, whereas in the East, in countries such as China, Japan, parts of Africa and India squamous cell cancers predominate.^1-4 The exact reasons for this are still unknown, but as per latest evidence it is likely to be a combination of environmental factors, dietary habits and genetics.^1,5,6

Need for Screening

Esophageal cancers carry a high mortality with estimated survival of 20% at 5 years, mainly due to delay in diagnosis.⁷ Majority of the cancers, even in developed countries are diagnosed in stage III and only 15% to 30% are eligible for curative intent therapy.^7,8 The large difference in stage-wise survival of esophageal cancer indicates that disease detected earlier has better prognosis. International data used for staging has shown that T1 lesions have a 5-year OS of >90%.^8,9

Squamous cancers of the esophagus may be considered amenable to screening as they meet the criteria for screening to be effective such as

(1) High incidence of disease—disease of public health importance.

(2) Validated test that can detect the disease at an early stage.

(3) Detectable preclinical phase.

(4) Effective treatment option at an early stage that can prolong survival. (Adapted from Wilson and Jungner’s criteria for screening).¹⁰

Applying these principles to squamous cell cancers of the esophagus (ESCC), age-standardized incidence rate of esophageal cancers in Eastern Asia is 18.2 per100 000 population, with a predominance of squamous cell cancers,³ making it a disease of high incidence and of public health importance. Certain rural regions in China such as Cixian and Yanting have an incidence of >150 per100 000 population.^3,11

Natural History and Pre-Cursor Lesions

Presence of detectable pre-cursor lesions are essential for screening to be successful.^8,10 Studies from China have shown that squamous dysplasia is a definite precursor lesion for ESCC.^5,8,12

Wang et al performed a sub-set analysis of the Linxian Nutritional Intervention Study.¹³ They followed up 682 patients who had undergone endoscopy and biopsy from the esophagus for a median of 13.5 years. Patients who became symptomatic were biopsied again. Biopsy results were then compared and the risk of developing malignancy was analyzed. In patients with a biopsy report of carcinoma-in-situ and severe dysplasia, there was a 74% risk of developing malignancy. For patients who had mild and moderate dysplasia, the risk was 24% and 50% respectively. In contrast, it 15% in those with basal cell hyperplasia and 8% for those with esophagitis

In a prospective endoscopic study conducted in rural China from 2006 to 2015 where 1753 cases were followed up for 2.9 years(median), the authors found increased risk of progression to esophageal squamous cell carcinoma with higher grades of dysplasia and also demonstrated a 2.6 times increased risk of developing ESCC in males and 1.2 times increased risk in elderly participants(>50 years).¹²

Lu et al followed up patients with “atypia” and demonstrated that patients with atypia had a 2.9 times higher risk of developing ESCC compared to normal controls.¹⁴ Wang et al published large studies involving >3000 patients demonstrating the feasibility of using Lugol chromo-endoscopy for screening of pre cursor lesions, described their treatment and reported optimal survival outcomes.^13,15-17 A few studies from Iran have also demonstrated the high incidence of esophageal pre cursor lesions in high-risk areas and the feasibility of using balloon cytology to detect them.^18,19

Who Needs to be Screened?

Smoking and alcohol consumption are established risk factors world over for ESCC.¹ Apart from these, there is evidence from high incidence areas regarding consumption of hot liquids, salted/pickled or fermented food, diet lacking in fresh fruits and vegetables, presence of achalasia cardia, family history of ESCC, ingestion of caustic substances and previous history of head and neck cancers conferring a higher risk of developing ESCC as shown in Table 1.^5,6,20 These factors play a major role in participant selection for screening.

Table 1.

Risk Factors for ESCC.

Sr.no	Risk factors	Population	Relative risk
1.	Smoking^1,4	Chinese, African-American, Indian	4-8
2.	Alcohol¹	African-American, Caucasian	4-8
3.	Poverty²¹	African-American	2-4
4.	Achalasia²²	Swedish	4-8
5.	Caustic/corrosive injury to the esophagus²³	Chinese	>8
6.	Nonepidermolytic palmoplantar keratoderma (tylosis)²⁴	Caucasian	>8
7.	Plummer-Vinson syndrome²⁵	Caucasian	>8
8.	History of head and neck cancer²⁶	Caucasian	>8
9.	History of breast cancer treated with radiotherapy²⁵	Caucasian	4-8
10.	Frequent consumption of hot beverages¹⁵	Iranian, Chinese, South American	<2
11.	Nutritional deficiencies⁶	Chinese	<2

Human papilloma viruses have been shown to play an important role in pathogenesis of other squamous cell cancers, however in esophagus, the evidence is inconclusive.²⁷

Most of the studies done on screening are from high incidence areas, where the entire adult population between the age group of 40 and 69 years have been screened.^28-36 In an ongoing RCT in China,³³ considering the risk factors for ESCC, in non-endemic areas- heavy smokers (>10 pack years), those with a family history of ESCC in first degree relatives, heavy alcohol consumers (>28 g/day for 10 years), history of esophagitis and reflux disease, eating salted food/pickled food at least once a week were used as inclusion criteria to select patients for screening. Using the above criteria, the detection rate in non-high-risk areas was about 0.9% and in high-risk areas where all adults between 40 and 69 years were included, it was 0.8%.³³ This can be considered an average pick-up rate, when compared to screening trials conducted for other common cancers, such as the National Lung Screening Trial(NLST), which had a pick-up rate of 2.6%.³⁷

As most of the data is from China as shown in Table 3, it would be difficult to extrapolate this data to other regions. Hence, patient selection needs to be specific to the population that we need to screen and criteria will have to be based on data available regarding risk factors in that region. However, based on available data—old age (>60 years), smoking and alcohol consumption seem to be common risk factors across regions.¹

Modalities for Screening

Standard Endoscopy

Fiber-optic endoscopy as of today, is widely available and is the first choice of investigation in patients with symptoms suggestive of ESCC. Gruber et al³⁸ from Brazil, published their results for detection of esophageal dysplasia by conventional white-light endoscopy(standard), the sensitivity was 40.6% and specificity was 76.8%. They concluded that standard endoscopy is not accurate enough for detection of pre-cancerous lesions.

Chromo-Endoscopy With Lugol’s Iodine

The basic principle of using Lugol’s iodine is that abnormal squamous cells do not take up iodine staining, where as normal squamous epithelium of the esophagus does as shown in Figure 3.^39,40 Abnormal squamous epithelium could be either frank malignancy, carcinoma in-situ, dysplasia or esophagitis.^39-42 The stain helps to choose the site of biopsy. In this procedure, 10 to 40 mL of 0.3% to 0.5% of Lugol’s iodine is sprayed on the esophageal mucosa and in 5 to 8 minutes differential staining occurs. Areas which do not take up the stain are biopsied adequately.^39,40

Figure 3.

Lugol’s chromo-endoscopy—left image—iodine staining demonstrated over normal mucosa. Right image—planning for biopsy from unstained area. (Borrowed with permission from Prof. Jacques Bergman, Amsterdam Medical Center).

Misumi from Japan first reported this technique,⁴⁰ However, it was the landmark study by Dawsey et al³⁹ conducted in Linxian province in China, that demonstrated the effectiveness of this technique in a large population to pick up pre cursor lesions.

In a French study by Dubuc et al,⁴³ using Lugol’s iodine they were able to demonstrate superiority over conventional endoscopy. Patients were divided into 4 groups—(1) previous history of head and neck cancers, (2) alcohol and tobacco addicts, (3) alcoholic pancreatitis, and (4) alcoholic cirrhosis. Conventional endoscopy was able to pick up 35 abnormal lesions compared to chromo-endoscopy which picked up 67 lesions. The difference was more apparent for early pre cursor lesion such as dysplasia and carcinoma in-situ.

Zeng et al recently conducted a cluster RCT in China, where 345 villages in high incidence areas underwent randomization. All adults aged between 40 and 69 years old, who had no past history of cancer and had not received endoscopy in the past 3 years were invited to participate in the trial. In total,37 922 subjects underwent chromo-endoscopy with Lugol’s iodine and 528 (1.8%) positive cases were detected. Of the invited participants, only 45% consented for endoscopy and there were no significant serious adverse events associated with this procedure. This large study demonstrated the safety and efficacy of chromo-endoscopy with Lugol’s iodine in a community setting.³³

Chromo-endoscopy with Lugol’s iodine appears to be effective, but endoscopy it is still an invasive procedure and compliance of asymptomatic patients is still low. It requires a clinic or a hospital setting and an experienced operator, especially to pick up pre cursor lesions.⁴⁴

Chinese Cytology Technique

Innovative, low-cost technique developed in China in the 1950s.⁴⁵ It involves using a balloon catheter covered with a cotton web as shown in Figure 4. The catheter is inserted in a similar fashion to a conventional naso-gastric tube (blind procedure) (Figure 2). Once the balloon is in the gastric mucosa, it is inflated with a syringe and then withdrawn across the esophagus, till resistance is encountered at the upper esophageal sphincter. At this point the balloon is deflated and withdrawn through the oral cavity. The sample then obtained is put on a glass slide and stained by the Papincolou method.

Figure 4.

Picture demonstrating Chinese balloon cytology—Left upper corner—Prof. Shen Q taking a cytology exam, right upper corner—Prof Dawsey being administered a balloon test by Prof. Shen. Other images—various types of balloons and equipment used for the procedure. (Picture borrowed with permission from Prof. Sanford Dawsey, NCI).

The samples are then graded like other squamous lesions using the Bethesda system⁴⁶—atypical squamous cells of undetermined significance (ASCUS), low grade squamous intraepithelial neoplasia (LSIL), high grade squamous intra epithelial neoplasia (HSIL).

Large studies from China involving more than 10 000 patients^15,31,32,47 have shown that the yield of cells with this technique is adequate, but sensitivity only ranges from 39% to 62%. Even though this could pick up some early precursor lesions, accuracy was not optimal for this technique to be recommended as the standard.

Improving Sensitivity Using Molecular Markers

To improve sensitivity, various authors have analyzed immunohistochemical and molecular markers in cytology specimens. Methylated DNA markers (MDM) have shown promise in recent studies. An international multi-nation study involving subjects from China, United States and Iran, where 430 samples were analyzed for MDM has shown promising results. In this study, balloon cytology samples from China were also included. Statistical modeling was done and area under the RoC curve was calculated. In all 3 models, the AUC was >0.90. Another interesting finding in the Chinese cytology specimens was that the degree of methylation corresponded to the grades of dysplasia.⁴⁸ A pilot study in China published in 2022 also showed promising results when p16 alone was used as a methylation marker.⁴⁹

The Chinese cytology technique has potential to be an ideal screening technique. However, compliance and acceptance rates may vary across regions and using molecular markers for screening might not be a cost-effective option.

Cytosponge Technique

There are various other devices designed based on similar principles

The Cytosponge technique developed by Professor Fitzgerald from UK,⁵⁰ has shown a lot of promise in screening for Barret’s Esophagus (BE) in a GERD population. The combination of Cytosponge and trefoil factor 3(TFF3) increases the detection of Barret’s esophagus by 10.6 times in a primary care setting.⁵¹ It consists of a gelatin capsule attached to a string; the capsule contains a compressed foam sphere. The patient is expected to swallow the capsule whole, while holding the string. The capsule dissolves in the stomach and the sponge expands, then the sponge is pulled up through the esophagus and oral cavity.⁵⁰ In an Iranian study of 301 participants, cytosponge combined with p53 staining showed a sensitivity of 100% and a specificity of 97%.⁵² Larger studies are required to assess its feasibility and cost effectiveness for screening.

Gao et al used artificial intelligence and machine learning techniques to select high risk patients and analyze the cytology specimens obtained by cytosponge and reported that more than 90% of screening endoscopies could be avoided.⁵³

Image Enhanced Endoscopy—Narrow Band Imaging (NBI) and Autofluorescence

These are newer endoscopic techniques that are expensive and may not be cost-effective for mass screening, however, they have shown promising results.

Narrow Band Imaging is generally combined in modern endoscopic units, a single twist of the knob or pressing of a button can introduce the NBI filter.⁵⁴ In this real-time imaging, abnormal esophageal mucosa is seen as brownish spots, sensitivity in expert hands has been demonstrated to be in the range of 85% to 90%.⁵⁵ Autofluorescence is based on the principle of differential absorption of fluorescent light between normal and abnormal mucosa, but sensitivity and specificity for esophageal lesions is lesser than NBI.²⁰ In a review article by Chung et al,²⁶ the pooled average risk of developing an esophageal second primary in a patient with head and neck cancer was 8.1% (28 studies, >4000 patients). With the addition of enhanced imaging (chromoendoscopy, NBI) detection rates were increased by 5% to 10%.^26,56

Microendoscopy and endocytoscopy are other promising image enhancing technologies that are in development and may become important in the near future.²⁰

Less Invasive Endoscopic Modalities

Transnasal endoscopy (TNE) uses a thin scope, which is inserted through the nose, this avoids touching the base of tongue, hence reduces gag reflex.²⁰ Various randomized trials and meta-analysis have concluded that TNE is equivalent to conventional endoscopy for endoscopic diagnosis, but is inferior for histologic diagnosis, possibly due to inferior image quality.⁵⁷ However, patient acceptance is higher for TNE compared to conventional endoscopy. Wang et al and Arantes et al have shown that TNE is also safe and feasible for detecting ESCC.^58,59

Capsule endoscopy has shown some promise in screening for adenocarcinoma.⁵¹ A meta-analysis of 9 pooled studies showed a sensitivity of 77% and specificity of 86% for diagnosing Barrett’s Esophagus in GERD patients.⁶⁰ However, as per Western data, the cost of capsule endoscopy appears to be prohibitive for mass screening⁵¹

However, capsule endoscopy has not been used or tested for screening in squamous cell cancers.

Non-Invasive Tests/Non-Endoscopic Methods

These tests are hypothesized to be effective for mass screening—as they don’t require a skilled operator, likely to be cost effective and have higher patient acceptability.

Serum based bio-markers—require only venous blood sampling from the patient. Auto-antibodies to tumor associated antigens (TAA) have been tested for diagnosing ESCC—A 6-panel autoantibody test in 237 patients demonstrated a poor sensitivity of 45%.⁶¹ Circulating microRNA (miRNAs) have been extensively studied for diagnosing ESCC. A recent meta-analysis showed a pooled sensitivity of 79.9% and specificity of 81.3% for diagnosis of ESCC.⁶² Further studies are required to validate it in a screening population. Salivary biomarkers also have shown some promise in recent studies, but are yet to be tested for screening.⁶³

The relative merits and demerits of these modalities have been summarized in Table 2.

Table 2.

Pros and Cons of Screening Methods.

Sr no	Screening modality	Advantages	Disadvantages
1.	Chinese balloon cytology	CheapWidely availableGood specificity	Sensitivity ranges from 39% to 62%-not adequate for screeningBlind techniquePatient discomfort
2.	Conventional white light endoscopy	Visualizes mucosaWidely available	Sensitivity (40%) and specificity (70%) not adequate for screeningInvasive methodNeeds clinical infrastructure and trained personnel.
3.	Chromo-endoscopy with Lugol Iodine	Visualizes mucosaLugol Iodine dye is available easilyGood sensitivity and specificity to pick up pre cursor lesions	Requires clinical infrastructureCostlier than Chinese Cytology techniqueRequires trained personnelOperator-dependent
4.	Endoscopy with narrow band imaging	Good sensitivity and specificity for pre cursor lesions	CostlyRequires trained personnelOperator-dependent
5.	Transnasal endoscopy	Does not require sedation	Not widely available, scant data in ESCC
6.	Endocytoscopy	Direct microscopic view of mucosa, potential to avoid tissue biopsy	Requires trainingPathological expertiseScant data available for precursor lesions and ESCC
7.	Microendoscopy	Same advantages as endocytoscopyBut equipment is portable and added to standard endoscopy	Small field of viewRequires expertiseCost effectiveness yet to be determined
8.	Non-invasive methods	Requires minimal clinical infrastructureNon invasiveCheapMore easy to administer over large populations compared to screening methods	Data is not yet strong enough to recommend routine useCost effectiveness yet to be determinedSensitivity and specificity still below invasive methodsSophisticated laboratory techniques may not be widely available

Is There Evidence at Present to Support Screening?

The evidence to support screening for squamous cell cancer of the esophagus is insufficient at present. However, as of today, 3 large randomized controlled trials are underway in high-risk areas of China as shown in Table 3. One of them is a cluster randomized controlled trial (RCT) of 345 eligible clusters,³³ they have recruited 145 956 participants from high risk and non-high-risk areas to screen for esophageal and gastric cancers. Chromo-endoscopy with Lugol’s iodine for esophageal and indigo-carmine dye for gastric cancers was used for detection of early lesions.

Table 3.

Summary of Major Screening Studies on ESCC.

Sr no	First author, year of publication, country	Screening modality	No of participants	Type of study	Outcomes
1.	Lu, 1988, China¹⁴	Chinese balloon cytology	1010	Prospective cohort- single arm interventional trial	2.39 Times higher risk of developing ESCC after diagnosis of marked atypia
2.	Wang et al, 2005, China¹³	Chinese balloon cytology	2273	Single arm prospective interventional trial	4.2%-Detection rate of balloon cytology-pre cursor lesion
3.	Wei et al, 2015, China⁶⁴	Lugol chromo-endoscopy	3319-Screening797-Control	Non randomized clinical trial	2.6% Deduction in mortality from ESCC in screening group.
3.	He et al, 2019, (ESECC trial), China²⁸	Lugol chromo endoscopy	17151-Screening16797- No screening	Cluster RCT	Incidence of high-grade dysplasia744/100000- 0.7%
4.	Zeng et al, 2020, China³³	Lugol chromo-endoscopy	75421-Screening74535-Control	Cluster RCT	Detection rate of 0.7% for ESCC4.5% for precursor lesions
5.	Xiao et al, 2020, China³⁴	Lugol chromo-endoscopy	10416-Screening9565-Control	Cluster RCT	Detection rate of 1.21% for esophageal precursor lesions
6.	Yu et al, 2022, China³⁵	Lugol chromo-endoscopy	1957	Prospective cohort-single arm study	4.39% Detection rate for esophageal pre cursor lesions

As per the initial results, the detection rate was 0.7% in non-high-risk areas and 0.8% in high-risk areas. Majority of the cases detected (92.9%) were early stage (0/I). Long term results are awaited.

The other large cluster RCT underway in China (Hua County, Henan Province) is the ESECC trial—Efficacy of endoscopic screening for esophageal cancer in China.²⁸ Seventeen thousand one hundred fifty-one participants have been recruited in the screening arm and 16 797 in the control arm. Participants in the screening arm underwent one-time Lugol chromo-endoscopy. Initial results showed a detection rate of 0.74%. In this study 113 lesions were detected which were classified as high grade and 69.9% were early-stage cancers (stage 0/I). Long term and detailed results are awaited.

A large non randomized interventional study by Wei et al⁶⁴ conducted in China demonstrated 1.7% reduction in mortality. In this study 3319 participants underwent one-time Lugol chromo-endoscopy and the control arm consisted of 797 participants from 10 different villages from another geographical region who were under observation only. At 10 years of follow up the screened arm had a 3.35% mortality rate from ESCC compared to 5.05% in the control arm (P < .001).

Cost Effectiveness

Li et al⁶⁵ using data from the ESECC trial estimated the cost of screening with chromoendoscopy with a valid pathological diagnosis as 196$ and the cost of detecting one early-stage esophageal cancer was37 687$. Considering the per capita income in rural China to be around 5000$, the cost of screening endoscopy was estimated to be around 3.5% to 4% of the per capita income, which was considered to be quite a significant burden on the exchequer. By using precision screening methodology and selecting only high-risk cases to be screened the costs could be reduced by around 25% to 30%.

Xia et al⁶⁶ also estimated the cost effectiveness of endoscopic screening for esophageal and gastric cancers in high-risk areas in China. They used a Markov model and estimated that endoscopic screening improved effectiveness by 1087 to 10362 quality adjusted life years (QALYs) leading to incremental cost effectiveness ratio (ICERs) between 1343 and 3035 $ per QALY. They concluded that the most cost-effective strategy would be to screen the high-risk population between the age group of 40 and 69 years every 2 years

Conclusions

To summarize, screening for esophageal squamous cancers appears to be feasible in high incidence areas. Patient selection is still controversial, older age, smoking and alcohol consumption seem to be established risk factors, but other environmental and dietary factors need to be quantified and considered. Amongst the various modalities available for screening, Lugol chromoendoscopy appears to be the method of choice, especially with regards to accuracy and cost-effectiveness. Evidence from prospective studies and initial results from Chinese trials do not provide robust evidence for screening, but they demonstrate its safety and feasibility. Further long-term data on the effect on mortality is still awaited. Screening high-risk individuals has been adopted across many cancers and is a continuously evolving field for esophageal squamous carcinoma. Lack of a cost-effective and non-invasive suitable modality seems to be the major hurdle in generating evidence for screening this disease.

Footnotes

Acknowledgements

Prof. Sanford Dawsey, NCI(USA), Prof. Jacques Bergman and Prof. Pengfei Xu for allowing to use their materials.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Kamangar

Nasrollahzadeh

Safiri

, et al. The global, regional, and national burden of oesophageal cancer and its attributable risk factors in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020;5(6):582-597. doi:10.1016/S2468-1253(20)30007-8

Bray

Ferlay

Soerjomataram

Siegel

Torre

Jemal

Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. doi:10.3322/caac.21492

Morgan

Soerjomataram

Rumgay

, et al. The global landscape of esophageal squamous cell carcinoma and esophageal adenocarcinoma incidence and mortality in 2020 and projections to 2040: new estimates from GLOBOCAN 2020. Gastroenterology. 2022;163(3):649-658.e2. doi:10.1053/j.gastro.2022.05.054

Liu

Qin

, et al. Epidemiology of esophageal cancer in 2020 and projections to 2030 and 2040. Thorac Cancer. 2023;14(1):3-11. doi:10.1111/1759-7714.14745

Yang

Chen

Etiology and prevention of esophageal cancer. Gastrointest Tumors. 2016;3(1):3-16. doi:10.1159/000443155

Wang

Abnet

Qiao

YL.

What have we learned from Linxian esophageal cancer etiological studies?

Thorac Cancer. 2019;10(5):1036-1042. doi:10.1111/1759-7714.13058

Arnold

Rutherford

Lam

Bray

Ervik

, Soerjomataram I. ICBP SURVMARK-2 online tool: International Cancer Survival Benchmarking. Lyon, France: International Agency for Research on Cancer. 2019. https://gco.iarc.fr/survival/survmark. Accessed May 20, 2023.

Lopes

Fagundes

. Esophageal squamous cell carcinoma - precursor lesions and early diagnosis. World J Gastrointest Endosc. 2012;4(1):9-16. doi:10.4253/wjge.v4.i1.9

Ancona

Rampado

Cassaro

, et al. Prediction of lymph node status in superficial esophageal carcinoma. Ann Surg Oncol. 2008;15(11):3278-3288. doi:10.1245/S10434-008-0065-1

10.

Wilson

JMG

Jungner

. Principles and practices of screening for disease. Geneva, Switzerland: World Health Organization; 1968. Report No.: Public Health Papers No. 34. http://whqlibdoc.who.int/php/WHO_PHP_34.pdf.

11.

Hou

Qiao

, et al. An analysis of esophageal cancer incidence in Cixian county from 1974 to 1996. World J Gastroenterol. 2003;9(2):209-213. doi:10.3748/WJG.V9.I2.209

12.

Gao

Zhang

, et al. Progression of precancerous lesions of esophageal squamous cell carcinomas in a high-risk, rural Chinese population. Cancer Med. 2023;12(2):1791-1800. doi:10.1002/CAM4.4965

13.

Wang

Abnet

Shen

, et al. Histological precursors of oesophageal squamous cell carcinoma: results from a 13 year prospective follow up study in a high risk population. Gut. 2005;54(2):187. doi:10.1136/GUT.2004.046631

14.

Yang

Dong

Sang

. A prospective study of esophageal cytological atypia in Linxian county. Int J Cancer. 1988;41(6):805-808. doi:10.1002/IJC.2910410605

15.

Wang

. 30-year experiences on early detection and treatment of esophageal cancer in high risk areas. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2001;23(1):69-72.

16.

Wang

Zhou

Feng

, et al. Intervention and follow-up on human esophageal precancerous lesions in Henan, northern China, a high-incidence area for esophageal cancer. Gan To Kagaku Ryoho. 2002;29(Suppl 1):159-172.

17.

Wang

Jiao

Chang

, et al. Long-term results of operation for 420 patients with early squamous cell esophageal carcinoma discovered by screening. Ann Thorac Surg. 2004;77(5):1740-1744. doi:10.1016/j.athoracsur.2003.10.098

18.

Saidi

Malekzadeh

Sotoudeh

, et al. Endoscopic esophageal cancer survey in the western part of the Caspian Littoral. Dis Esophagus. 2002;15(3):214-218. doi:10.1046/j.1442-2050.2002.00250.x

19.

Sepehr

Razavi

Saidi

Salehian

Rahmani

Shamshiri

. Esophageal exfoliative cytology samplers. A comparison of three types. Acta Cytol. 2000;44(5):797-804. doi:10.1159/000328564

20.

Codipilly

Qin

Dawsey

, et al. Screening for esophageal squamous cell carcinoma: recent advances. Gastrointest Endosc. 2018;88(3):413-426. doi:10.1016/J.GIE.2018.04.2352

21.

Morris Brown

Hoover

Silverman

, et al. Excess incidence of squamous cell esophageal cancer among US Black men: role of social class and other risk factors. Am J Epidemiol. 2001;153(2):114-122. doi:10.1093/aje/153.2.114

22.

Torres-Aguilera

Remes Troche

. Achalasia and esophageal cancer: risks and links. Clin Exp Gastroenterol. 2018;11:309-316. doi:10.2147/CEG.S141642

23.

Chen

Yang

Pan

Lin

Hung

. The prevalence of esophageal cancer after caustic and pesticide ingestion: a nationwide cohort study. PLoS One. 2020;15(12):e0243922. doi:10.1371/journal.pone.0243922

24.

Risk

Mills

Garde

, et al. The tylosis esophageal cancer (Toc) locus: more than just a familial cancer gene. Dis Esophagus. 1999;12(3):173-176. doi:10.1046/j.1442-2050.1999.00042.x

25.

Enzinger

Mayer

. Esophageal Cancer. N Engl J Med. 2003;349(23): 2241-2252.

26.

Chung

Liao

, et al. Endoscopic screening for second primary tumors of the esophagus among head and neck cancer patients. Front Oncol. 2022;12:906125. doi:10.3389/FONC.2022.906125

27.

Patel

Yadlapati

. Salivary biomarkers and esophageal disorders. Dis Esophagus. 2022;35(7):1-7. doi:10.1093/DOTE/DOAC018

28.

Liu

, et al. Efficacy of endoscopic screening for esophageal cancer in China (ESECC): design and preliminary results of a population-based randomised controlled trial. Gut. 2019;68(2):198-206. doi:10.1136/gutjnl-2017-315520

29.

Chen

Guan

, et al. The national cohort of esophageal cancer-prospective cohort study of esophageal cancer and precancerous lesions based on high-risk population in China (NCEC-HRP): study protocol. BMJ Open. 2019;9(4):e027360. doi:10.1136/BMJOPEN-2018-027360

30.

Chen

Ren

, et al. Selection of high-risk individuals for esophageal cancer screening: a prediction model of esophageal squamous cell carcinoma based on a multicenter screening cohort in rural China. Int J Cancer. 2021;148(2):329-339. doi:10.1002/IJC.33208

31.

Shen

Wang

Liu

, et al. Cytologic screening for esophageal cancer: results from 12,877 subjects from a high-risk population in China. Int J Cancer. 1993;54(2):185-188. doi:10.1002/IJC.2910540204

32.

Wang

Yang

Fan

, et al. Cytological screening and 15 years’ follow-up (1986–2001) for early esophageal squamous cell carcinoma and precancerous lesions in a high-risk population in Anyang County, Henan Province, Northern China. Cancer Detect Prev. 2005;29(4):317-322. doi:10.1016/J.CDP.2005.06.004

33.

Zeng

Sun

Cao

, et al. Initial results from a multi-center population-based cluster randomized trial of esophageal and gastric cancer screening in China. BMC Gastroenterol. 2020;20:398.

34.

Xiao

Yan

Chen

, et al. Community-based upper gastrointestinal cancer screening in a randomized controlled trial: baseline results in a non-high-incidence area. Cancer Prev Res. 2020;13(3):317-328. doi:10.1158/1940-6207.CAPR-19-0422

35.

Zuo

, et al. Outcomes of upper gastrointestinal cancer screening in high-risk individuals: a population-based prospective study in Northeast China. BMJ Open. 2022;12(2):e046134. doi:10.1136/bmjopen-2020-046134

36.

Yang

Huang

, et al. Screening for oesophageal cancer. Cochrane Database Syst Rev. 2012;12:CD007883. doi:10.1002/14651858.CD007883.PUB2

37.

de Koning

van der Aalst

de Jong

, et al. Reduced lung-cancer mortality with volume CT screening in a randomized trial. N Engl J Med. 2020;382(6):503-513.

38.

Grüber

de Barros

Pütten

, et al. Esophageal dysplasia and chronic esophagitis: detection at upper gastrointestinal tract endoscopy. Arq Gastroenterol. 1998;35(4):258-263.

39.

Dawsey

Fleischer

Wang

, et al. Mucosal iodine staining improves endoscopic visualization of squamous dysplasia and squamous cell carcinoma of the esophagus in Linxian, China. Cancer. 1998;83(2):220-231. doi:10.1002/(SICI)1097-0142(19980715)83:2<220::aid-cncr4>3.0.CO;2-U

40.

Misumi

Harada

Murakami

, et al. Role of Lugol dye endoscopy in the diagnosis of early esophageal cancer. Endoscopy. 1990;22(1):12-16. doi:10.1055/s-2007-1012779

41.

Freitag

Barros

Kruel

, et al. Esophageal dysplasias are detected by endoscopy with Lugol in patients at risk for squamous cell carcinoma in southern Brazil. Dis Esophagus. 1999;12(3):191-195. doi:10.1046/J.1442-2050.1999.00046.X

42.

Wang

Liu

Hao

, et al. A comparative study of endoscopic image stained by iodine and histopathology in early esophageal cancer and precancerous lesions (dysplasia). Zhonghua Zhong Liu Za Zhi. 2004;26(6):342-344.

43.

Dubuc

Legoux

Winnock

, et al. Endoscopic screening for esophageal squamous-cell carcinoma in high-risk patients: a prospective study conducted in 62 French endoscopy centers. Endoscopy. 2006;38(7):690-695. doi:10.1055/S-2006-925255

44.

Kolb

Davis

Williams

Holub

Shaheen

Wani

. Wide variability in dysplasia detection rate and adherence to Seattle protocol and surveillance recommendations in Barrett’s esophagus: a population-based analysis using the GIQuIC National Quality Benchmarking Registry. Am J Gastroenterol. 2023;118(5):900-904. doi:10.14309/ajg.0000000000002102

45.

Dawsey

Shen

Nieberg

, et al. Studies of esophageal balloon cytology in Linxian, China. Cancer Epidemiol Biomarkers Prev. 1997;6:121-130.

46.

Smith

. Bethesda 2001. Cytopathology. 2002;13(1):4-10. doi:10.1046/j.1365-2303.2002.00397.x

47.

Liu

Shen

Dawsey

, et al. Esophageal balloon cytology and subsequent risk of esophageal and gastric-cardia cancer in a high-risk chinese population. Int J Cancer. 1994;57(6):775-780. doi:10.1002/IJC.2910570603

48.

Qin

Taylor

Bamlet

, et al. Methylated DNA markers of esophageal squamous cancer and dysplasia: an international study. Cancer Epidemiol Biomarkers Prev. 2020;29(12):2642-2650. doi:10.1158/1055-9965.EPI-20-0616

49.

Fan

Qin

Zhou

, et al. Feasibility of using P16 methylation as a cytologic marker for esophageal squamous cell carcinoma screening: a pilot study. Cancer Med. 2022;11(21):4033-4042. doi:10.1002/cam4.4718

50.

Kadri

SR Lao-Sirieix

O’Donovan

, et al. Acceptability and accuracy of a non-endoscopic screening test for Barrett’s oesophagus in primary care: cohort study. BMJ. 2010;341(7773):595. doi:10.1136/BMJ.C4372

51.

Offman

Fitzgerald

. Alternatives to traditional per-oral endoscopy for screening. Gastrointest Endosc Clin N Am. 2017;27(3):379-396. doi:10.1016/j.giec.2017.02.002

52.

Roshandel

Merat

Sotoudeh

, et al. Pilot study of cytological testing for oesophageal squamous cell dysplasia in a high-risk area in Northern Iran. Br J Cancer. 2014;111(12):2235-2241. doi:10.1038/bjc.2014.506

53.

Gao

Xin

Lin

, et al. Machine learning-based automated sponge cytology for screening of oesophageal squamous cell carcinoma and adenocarcinoma of the oesophagogastric junction: a nationwide, multicohort, prospective study. Lancet Gastroenterol Hepatol. 2023;8:432-445. doi:10.1016/s2468-1253(23)00004-3

54.

Gono

. Narrow band imaging: technology basis and research and development history. Clin Endosc. 2015;48(6):476-480. doi:10.5946/ce.2015.48.6.476

55.

Nagami

Tominaga

Machida

, et al. Usefulness of non-magnifying narrow-band imaging in screening of early esophageal squamous cell carcinoma: a prospective comparative study using propensity score matching. Am J Gastroenterol. 2014;109(6):845-854. doi:10.1038/ajg.2014.94

56.

Moura

Kuboki

Baba

, et al. Long-term results of an endoscopic screening program for superficial esophageal cancer in patients with head and neck squamous cell carcinoma. Endosc Int Open. 2022;10(2):E200. doi:10.1055/A-1675-2334

57.

Sami

Subramanian

Ortiz-Fernández-Sordo

, et al. Performance characteristics of unsedated ultrathin video endoscopy in the assessment of the upper GI tract: systematic review and meta-analysis. Gastrointest Endosc. 2015;82(5):782-792. doi:10.1016/J.GIE.2015.07.016

58.

Arantes

Albuquerque

Salles

, et al. Effectiveness of unsedated transnasal endoscopy with white-light, flexible spectral imaging color enhancement, and lugol staining for esophageal cancer screening in high-risk patients. J Clin Gastroenterol. 2013;47(4):314-321. doi:10.1097/MCG.0b013e3182617fc1

59.

Wang

Lee

Wang

, et al. Use of transnasal endoscopy for screening of esophageal squamous cell carcinoma in high-risk patients: yield rate, completion rate, and safety. Dig Endosc. 2014;26(1):24-31. doi:10.1111/den.12053

60.

Bhardwaj

Hollenbeak

Pooran

Mathew

. A meta-analysis of the diagnostic accuracy of esophageal capsule endoscopy for Barrett’s esophagus in patients with gastroesophageal reflux disease. Am J Gastroenterol. 2009;104(6):1533-1539. doi:10.1038/AJG.2009.86

61.

Peng

Chen

, et al. Autoantibodies as potential biomarkers for the early detection of esophageal squamous cell carcinoma. Am J Gastroenterol. 2014;109(1):36-45. doi:10.1038/ajg.2013.384

62.

Liu

Tian

Xia

Ding

Cormier

. Circulating miRNAs as novel potential biomarkers for esophageal squamous cell carcinoma diagnosis: a meta-analysis update. Dis Esophagus. 2017;30(2):1-9. doi:10.1111/DOTE.12489

63.

Lin

Luo

, et al. A signature of saliva-derived exosomal small RNAs as predicting biomarker for esophageal carcinoma: a multicenter prospective study. Mol Cancer. 2022;21(1):21-13. doi:10.1186/s12943-022-01499-8

64.

Wei

Chen

, et al. Long-term follow-up of a community assignment, one-time endoscopic screening study of esophageal cancer in China. World J Clin Oncol. 2015;33(17):1951-1957. doi:10.1200/JCO.2014.58.0423

65.

Guo

, et al. Estimation of cost for endoscopic screening for esophageal cancer in a high-risk population in rural China: results from a population-level randomized controlled trial. Pharmacoeconomics. 2019;37(6):819-827. doi:10.1007/S40273-019-00766-9

66.

Xia

Zeng

Liu

, et al. Estimated cost-effectiveness of endoscopic screening for upper gastrointestinal tract cancer in high-risk areas in China. JAMA Netw Open. 2021;4:e2121403. doi:10.1001/jamanetworkopen.2021.21403

Screening for Esophageal Squamous Cell Carcinoma: A Review

Abstract

Keywords

Introduction

Need for Screening

Natural History and Pre-Cursor Lesions

Who Needs to be Screened?

Modalities for Screening

Standard Endoscopy

Chromo-Endoscopy With Lugol’s Iodine

Chinese Cytology Technique

Improving Sensitivity Using Molecular Markers

Cytosponge Technique

There are various other devices designed based on similar principles

Image Enhanced Endoscopy—Narrow Band Imaging (NBI) and Autofluorescence

Less Invasive Endoscopic Modalities

Non-Invasive Tests/Non-Endoscopic Methods

Is There Evidence at Present to Support Screening?

Cost Effectiveness

Conclusions

Footnotes

Acknowledgements

Declaration of Conflicting Interests

Funding

References